''' Expression of type 1 diabetes in genetically susceptible individuals is hypothesized to require an 'environmental trigger." However, study of environmental triggers in human populations, which are outbred and exposed at randomto microbiological agents, is difficult. The goal of this proposalis to understand in the rat how viral infection alters the immune system to lead to diabetes expression in genetically susceptible hosts. The proposed research builds on our extensive experience with the 8B rat model of autoimmune diabetes, the role of effector to regulatory T cell balances in regulating diabetes, and our extensive experience in the induction of diabetes in BBDR rats by viral infection. This proposal is based on exciting new developments: 1) unique molecular reagents,and lentivirus, siRNA, and shRNA technology;2) recently discovered novel factors importantfor generating and maintainingT cell anergy, and 3) availability of a non- lymphopenic rat model that expresses diabetes in response to toll-like receptor (TLR) ligation and viral infection[unreadable]determinants of diabetesinduction thought to be important in humans. We will use these novel resourcesto test our overall hypothesisthat viralinfection leads to expression of diabetes in genetically susceptible hosts by 1) inducing a transient lymphopenic state that 2) leads to decreasing regulatory T cell number or activity, and 3) preferential expansion of autoreactive T cells. Because our models are based on well defined environmental perturbants, we can now determineexactly how the immune response to infection with virus in geneticallysusceptible hosts leads to the expressionof diabetes. Specific Aim 1 is to define the.immune response of geneticallysusceptible and resistant hosts to viral infection. This fundamental information will be used to test our hypothesis that virus induced lymphopenia is a critical factor in the development of overt diabetes in hosts genetically predisposed to diabetes. Specific Aim 2 is to determine how virus infection modulates effector and regulatory T cells in diabetes-susceptible and resistant hosts. Wewill use new methodology to test our hypothesis that virus infection induces diabetes in genetically susceptible hosts by decreasing Treg activity while simultaneously inducing the expansion of autoreactive Tcells. Specific Aim 3 is to determine if virus infection modulates factors that control Tregs and anergic T cells. These studies will test our hypothesis that virus infection modulates a population of T cells that have both anergic and regulatory properties that are important in the expression of diabetes. Fulfilling these aims holds out the promise of identifying mechanisms relevantto the prevention of diabetes.